Partially absorbable fiber-reinforced composites for controlled drug delivery

ABSTRACT

This invention describes a partially absorbable, fiber-reinforced composite in the form of a ring, or a suture-like thread, with modified terminals for use as a controlled delivery system of at least one bioactive agent, wherein said composite comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric matrix containing an absorbable microparticulate ion-exchanger to modulate the release of the bioactive agent(s) for a desired period(s) of time at a specific biological site; this can be a vaginal canal, peritoneal cavity, scrotum, prostate gland, an ear loop or subcutaneous tissue. Such drug delivery systems can be used for the local administration of at least one bioactive agent, including those used as contraceptive, antimicrobial, anti-inflammatory and/or antiviral agents as well as for cancer treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/935,808, filed onSep. 8, 2004, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention deals with fiber-reinforced composite systems comprisingan absorbable fiber and a partially or essentially non-absorbable matrixfor use in the controlled release of one or more bioactive agent(s) atthe desired biological site, which may entail intravaginal,transcutaneous, intraperitoneal, and subcutaneous implantation of suchsystems. For the latter two routes of administration, the controlledrelease system is designed to be retrievable by withdrawing thenon-migrating end placed subcutaneously. The composite systems can belinear or circular and are so designed as to modulate the bioactiveagent(s) release profile as well as the mechanical properties, in part,through the controlled degradation of the absorbable reinforcing fiberand any other absorbable component that may be present in the matrix.

BACKGROUND OF THE INVENTION

Prior application of the same inventor have dealt with afiber-reinforced composite ring for the controlled release of at leastone bioactive agent incorporated in a biocompatible matrix reinforcedwith absorbable/biodegradable fibers capable of providing the mechanicalproperties needed for inserting and maintaining the ring in a bodycavity for a desired period of time. Such ring system can be used forthe intravaginal, intraperitoneal, and subcutaneous delivery of at leastone bioactive agent, including those used as contraceptives.

U.S. application Ser. No. 60/482,898 discloses a controlled drug releasedevice comprising a partially or fully absorbable, fiber-reinforcedcomposite ring system comprising an absorbable or non-absorbable matrix,an absorbable, reinforcing fibrous construct and an absorbable coatingto provide three modes of controlling the release of bioactive agentsand one mode for modulating the mechanical property of the ring in abody cavity during device functional use. For partially absorbable ringsystems, the drug release is dependent initially on the diffusion rateof the drug through the matrix and the absorbable coating. As the latterdegrades with time, the diffusion through the matrix prevails.Meanwhile, as the absorbable fibrous reinforcing construct undergoesdegradation with time, the mechanical strength of the composite ringdecreases to provide the desired mechanical strength retention profile.For a fully absorbable composite ring system, the degradation of thematrix offers an additional mode of controlling the release profile ascompared with the partially absorbable counterpart. In effect, theinvention of U.S. application Ser. No. 60/482,898 deals with afiber-reinforced composite ring system for the controlled release of atleast one bioactive agent comprising a biocompatible matrix reinforcedwith an absorbable/biodegradable fibrous construct capable of providingthe mechanical properties needed for inserting and maintaining said ringin a body cavity for the desired period of time, and wherein theabsorbable/biodegradable reinforcing fibers are made primarily from oneor more cyclic monomer(s) including glycolide, 1-lactide,.epsilon.-caprolactone, p-dioxanone, and trimethylene carbonate.

For the partially absorbable/biodegradable composite ring controlleddrug delivery system of U.S. application Ser. No. 60/482,898, thefiber-reinforced composite ring deals with the controlled release of atleast one bioactive agent and comprises a biocompatible matrixreinforced with absorbable/biodegradable fibers capable of providing themechanical properties needed for inserting and maintaining said ring ina body cavity for the desired period of time, wherein the reinforcingfibers are absorbable/biodegradable and the matrix isnon-absorbable/non-biodegradable, wherein the non-absorbable matrixcomprising a methacrylate polymer derived from at least one alkylmethacrylate monomer, and wherein the methacrylate polymer is derivedfrom one or more alkyl methacrylate monomer(s) and N-vinyl pyrrolidone.Alternatively, the matrix may comprise a cyclodextrin or cyclodextrinderivative.

Obviously, the partially absorbable/biodegradable composite ringcontrolled drug delivery system of U.S. application Ser. No. 60/482,898did not fully address the use of safe matrices such as silicones andpolyether urethanes, which are cited in the prior art as carriers ofmany bioactive agents. Accordingly, this invention addresses the use ofnon-absorbable/biostable polyether urethane or polysiloxanes as theprimary matrix component of the partially absorbable/biodegradablefiber-reinforced composite ring system comprising a drug solubilitymodifier for the controlled delivery of many bioactive agents includingthose cited in U.S. application Ser. No. 60/482,898.

SUMMARY OF THE INVENTION

The present invention deals, in general, with fiber-reinforced compositesystems comprising an absorbable fiber and a partially or essentiallynon-absorbable matrix for use in the controlled release of one or morebioactive agent(s) at the desired biological site, which may entailintravaginal, transcutaneous, intraperitoneal, and subcutaneousimplantation of such systems. For the latter two routes ofadministration, the controlled release system is designed to beretrievable by withdrawing the non-migrating end placed subcutaneously.The composite systems can be linear or circular and are so designed asto modulate the bioactive agent(s) release profile as well as themechanical properties, in part, through the controlled degradation ofthe absorbable reinforcing fiber and any other absorbable component thatmay be present in the matrix.

This invention addresses a partially absorbable, fiber-reinforcedcomposite for the controlled delivery of at least one bioactive agentcomprising an absorbable fiber construct capable of providingtime-dependent mechanical properties of a biostable elastomericcopolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site, wherein(1) the absorbable reinforcing fibers are formed from at least onecyclic monomer selected from the group consisting of glycolide,1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylene carbonate,and a morpholine-2,5-dione; and (2) the biostable matrix is made of apolyether urethane elastomer or a silicone elastomer, such as copolymerpolysiloxane, comprising dimethyl siloxane sequences, which can be madeof at least one of the Silastic® family of silicone elastomers. It ispreferred that the silicone elastomers contain evenly dispersedmicroparticulate silica to modulate its modulus.

A key aspect of this invention deals with a partially absorbable,fiber-reinforced composite for the controlled delivery of at least onebioactive agent comprising an absorbable fiber construct capable ofproviding time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site, whereinthe absorbable microparticulate ion-exchanger is a carboxyl-bearingpolyester based on at least one of the cyclic monomer selected from thegroup consisting of glycolide, 1-lactide, and a morpholine-2,5-dione andsaid partially absorbable, fiber-reinforced composite in the form of anintravaginal ring and the biological site is the vagina, wherein thereinforcing fibers are in the form of a circularly configured construct,with protruding side loops, of multifilament or monofilament yarn andwherein the matrix comprises an absorbable/biodegradable polymercomprising ester linkages, and the parent polymer is formed from atleast one cyclic monomer selected from the group consisting ofglycolide, 1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylenecarbonate, and a morpholine-2,5-dione.

A specific aspect of this invention deals with a partially absorbable,fiber-reinforced composite for the controlled delivery of at least onebioactive agent comprising an absorbable fiber construct capable ofproviding time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site where (1)the biostable matrix is a silicone elastomer, such as a copolymericpolysiloxane, comprising dimethyl siloxane sequences; and (2) theabsorbable microparticulate ion-exchanger is carboxyl-bearing polyesterbased on at least one of the cyclic monomer from the group consisting ofglycolide, 1-lactide, and a morpholine-2,5-dione. It is preferred thatthe fiber-reinforced composite ring comprises an absorbable polymericouter coating to modulate the release of at least one bioactive agent.

It is also preferred that the composite ring comprises (1) at least onebioactive agent comprises a contraceptive agent selected from the groupconsisting of spermiostatic agents, spermicidal agents, hormonal agents,non-steroidal agents, viscosity modifiers capable of increasing theviscosity of vaginal mucus; (2) at least one bioactive agent havingcontraceptive properties, which can be a combination of ascorbic acidand iron gluconate or a non-steroidal compound, such as tanapraget, thatis being evaluated clinically as an oral contraceptive with fewer sideeffects as compared with orally administered hormones (Chemical &Engineering News, Aug. 30, 2004, p. 8); (3) at least one bioactive agenthaving labor induction properties; (4) least one bioactive agent that isfor intravaginal and transvaginal prevention or treatment of aninfection selected from bacterial infections, fungal infections, viralinfections and parasitic infections; (5) at least one bioactive agentthat is for the treatment of cervical or ovarian cancer; (6) at leastone bioactive agent that is selected from the group consisting ofantifertility drugs, testosterone, testosterone precursors, spermicidalagents, sperm immobilizers, and bisphosphonate; (7) one bioactive agentthat is selected from the group consisting of antiprogestinic agents,anesthetic agents, analgesic agents, anti-inflammatory agents,antimicrobial agents, antiviral agents, and antipsychotic agents; and/or(8) at least one bioactive agent that is selected from the groupconsisting of monoclonal antibodies, recombinant immuno-modulatorvaccines, and hematopoietic growth factors.

A preferred aspect of this invention deals with a partially absorbable,fiber-reinforced composite for the controlled delivery of at least onebioactive agent comprising an absorbable fiber construct capable ofproviding time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site, whereinthe fiber-reinforced composite is an intravaginal ring comprising abioadhesive coating, and the matrix can be microporous or capable ofbeing microporous during end-use.

Another specific aspect of this invention deals with a partiallyabsorbable, fiber-reinforced composite for the controlled delivery of atleast one bioactive agent comprising an absorbable fiber constructcapable of providing time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site whereinsaid composite is in the form of a filament having a practicallyspherical head for outward retrieval from the biological site, whereinthe biological site is (1) a human peritoneal cavity with the head beingplaced subcutaneously; (2) a human scrotum or prostate gland with thehead being placed subcutaneously; or (3) the ear loop of an animal orhuman, with the head remaining ex vivo.

This invention also deals with a partially absorbable, fiber-reinforcedcomposite for the controlled delivery of at least one bioactive agentcomprising an absorbable fiber construct capable of providingtime-dependent mechanical properties of a biostable elastomericcopolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site whereinsaid composite is in the form of a suture-like strand for threadingthrough a biological site, wherein the biological site is (1) an animalskin or muscle with the terminals of the suture-like filament knotted atthe entrance and exit points of the skin for ease of removal after therequired period of time, or (2) a human skin or muscle with theterminals of the suture-like filament knotted at the entrance and exitpoints of the skin for ease of removal after the required period oftime.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This invention deals with a controlled drug delivery device comprising apartially absorbable, fiber-reinforced system comprising anon-absorbable elastomeric matrix, an absorbable fibrous construct tomodulate the device resilience and modulus with time during end-use, anabsorbable microparticulate polymeric ion-exchanger to modulate thesolubility of the drug through ionic interaction and/or creation ofmicroporosity in the matrix, and preferably a non-absorbablemicroparticulate, inorganic filler evenly dispersed in the elastomericmatrix to increase its modulus, and preferably, an absorbable surfacecoating to modulate the release of drug diffusion outward from thematrix. In effect, the device is so designed to allow for modulating theinitial and in-use modulus and resilience of the device by incorporating(1) an inert microparticulate inorganic filler to control the modulus;(2) an absorbable microparticulate ion-exchanger to control the initialmodulus, and in-use modulus wherein the ion-exchanger absorbs/dissolveswith or without ionic conjugation with active bioagent(s); and (3) anabsorbable fibrous construct to control the initial resilience andmodulus and modulate both properties as it absorbs during end use.Furthermore, the partially absorbable controlled drug delivery device isso designed to (1) allow the incorporation of a safe coloring additive,such as a dispersed dye, to render said device more recognizable; (2) anabsorbable microparticulate ion-exchanger that is capable of interactingwith the bioactive agent(s) to increase or decrease its solubility thatwill, in turn, affect its release profile; and (3) allow theincorporation of at least one bioactive agent that can be acontraceptive, antimicrobial, antifungal, antiviral, antibacterial,antineoplastic, and/or anti-inflammatory.

The present invention deals, in general, with fiber-reinforced compositesystems comprising an absorbable fiber and a partially or essentiallynon-absorbable matrix for use in the controlled release of one or morebioactive agent(s) at the desired biological site, which may entailintravaginal, transcutaneous, intraperitoneal, and subcutaneousimplantation of such systems. For the latter two routes ofadministration, the controlled release system is designed to beretrievable by withdrawing the non-migrating end placed subcutaneously.The composite systems can be linear or circular and are so designed asto modulate the bioactive agent(s) release profile as well as themechanical properties, in part, through the controlled degradation ofthe absorbable reinforcing fiber and any other absorbable component thatmay be present in the matrix.

This invention addresses a partially absorbable, fiber-reinforcedcomposite for the controlled delivery of at least one bioactive agentcomprising an absorbable fiber construct capable of providingtime-dependent mechanical properties of a biostable elastomericcopolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site, wherein(1) the absorbable reinforcing fibers are formed from at least onecyclic monomer selected from the group consisting of glycolide,1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylene carbonate,and a morpholine-2,5-dione; and (2) the biostable matrix is made of apolyether urethane elastomer or a silicone elastomer, such as copolymerpolysiloxane, comprising dimethyl siloxane sequences, which can be madeof at least one of the Silastic® family of silicone elastomers. It ispreferred that the silicone elastomers contain evenly dispersedmicroparticulate silica to modulate its modulus.

A key aspect of this invention deals with a partially absorbable,fiber-reinforced composite for the controlled delivery of at least onebioactive agent comprising an absorbable fiber construct capable ofproviding time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site, whereinthe absorbable microparticulate ion-exchanger is a carboxyl-bearingpolyester based on at least one of the cyclic monomer selected from thegroup consisting of glycolide, 1-lactide, and a morpholine-2,5-dione andsaid partially absorbable, fiber-reinforced composite in the form of anintravaginal ring and the biological site is the vagina, wherein thereinforcing fibers are in the form of a circularly configured construct,with protruding side loops, of multifilament or monofilament yarn andwherein the matrix comprises an absorbable/biodegradable polymercomprising ester linkages, and the parent polymer is formed from atleast one cyclic monomer selected from the group consisting ofglycolide, 1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylenecarbonate, and a morpholine-2,5-dione.

A specific aspect of this invention deals with a partially absorbable,fiber-reinforced composite for the controlled delivery of at least onebioactive agent comprising an absorbable fiber construct capable ofproviding time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site where (1)the biostable matrix is a silicone elastomer, such as a copolymericpolysiloxane, comprising dimethyl siloxane sequences; and (2) theabsorbable microparticulate ion-exchanger is carboxyl-bearing polyesterbased on at least one of the cyclic monomer from the group consisting ofglycolide, 1-lactide, and a morpholine-2,5-dione. It is preferred thatthe fiber-reinforced composite ring comprises an absorbable polymericouter coating to modulate the release of at least one bioactive agent.

It is also preferred that the composite ring comprises (1) at least onebioactive agent comprises a contraceptive agent selected from the groupconsisting of spermiostatic agents, spermicidal agents, hormonal agents,non-steroidal agents, viscosity modifiers capable of increasing theviscosity of vaginal mucus; (2) at least one bioactive agent havingcontraceptive properties, which can be a combination of ascorbic acidand iron gluconate or a non-steroidal compound, such as tanapraget, thatis being evaluated clinically as an oral contraceptive with fewer sideeffects as compared with orally administered hormones (Chemical &Engineering News, Aug. 30, 2004, p. 8); (3) at least one bioactive agenthaving labor induction properties; (4) least one bioactive agent that isfor intravaginal and transvaginal prevention or treatment of aninfection selected from bacterial infections, fungal infections, viralinfections and parasitic infections; (5) at least one bioactive agent isfor the treatment of cervical or ovarian cancer; (6) at least onebioactive agent that is selected from the group consisting ofantifertility drugs, testosterone, testosterone precursors, spermicidalagents, sperm immobilizers, and bisphosphonate; (7) one bioactive agentthat is selected from the group consisting of antiprogestinic agents,anesthetic agents, analgesic agents, anti-inflammatory agents,antimicrobial agents, antiviral agents, and antipsychotic agents; and/or(8) at least one bioactive agent that is selected from the groupconsisting of monoclonal antibodies, recombinant immunomodulatorvaccines, and hematopoietic growth factors.

A preferred aspect of this invention deals with a partially absorbable,fiber-reinforced composite for the controlled delivery of at least onebioactive agent comprising an absorbable fiber construct capable ofproviding time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site, whereinthe fiber-reinforced composite is an intravaginal ring comprising abioadhesive coating, and the matrix can be microporous or capable ofbeing microporous during end-use.

Another specific aspect of this invention deals with a partiallyabsorbable, fiber-reinforced composite for the controlled delivery of atleast one bioactive agent comprising an absorbable fiber constructcapable of providing time-dependent mechanical properties of a biostableelastomeric copolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site whereinsaid composite is in the form of a filament having a practicallyspherical head for outward retrieval from the biological site, whereinthe biological site is (1) a human peritoneal cavity with the head beingplaced subcutaneously; (2) a human scrotum or prostrate gland with thehead being placed subcutaneously; or (3) the ear loop of an animal orhuman, with the head remaining ex vivo.

This invention also deals with a partially absorbable, fiber-reinforcedcomposite for the controlled delivery of at least one bioactive agentcomprising an absorbable fiber construct capable of providingtime-dependent mechanical properties of a biostable elastomericcopolymeric matrix containing an absorbable microparticulateion-exchanging polymer to modulate the release of said bioactive agentfor the desired period of time at a specific biological site whereinsaid composite is in the form of a suture-like strand for threadingthrough a biological site, wherein the biological site is (1) an animalskin or muscle with the terminals of the suture-like filament knotted atthe entrance and exit points of the skin for ease of removal after therequired period of time, or (2) a human skin or muscle with theterminals of the suture-like filament knotted at the entrance and exitpoints of the skin for ease of removal after the required period oftime.

Additional illustrative examples associated with this invention areoutlined below.

EXAMPLE 1

Preparation of Acid-terminated Polyglycolide Cation-exchangingMicroparticulate (PG-61)

Glycolide was polymerized in the presence of glycolic acid and stannousoctanoate to produce low molecular weight, hydrolytically degradablepolyester PG-61, as described in U.S. Pat. No. 6,413,539. Purificationand reduction in size of PG-61 was also conducted as per U.S. Pat. No.6,413,539 teaching.

EXAMPLE 2

Preparation of 95/5 .epsilon.-Caprolactone/Glycolide Copolymer Coating(CT-1)

The CT-1 copolymer was prepared by the copolymerization of.epsilon.-caprolactone (0.625 mole) with glycolide (32.3 mmole) in thepresence of glycolic acid (3.756 mmole) as the initiator and stannousoctanoate (0.1247 mmole as 0.2M solution in toluene) as the catalyst.The polymerization was conducted in a mechanically stirred reactor undera dry nitrogen atmosphere at 150.degree. C. for 6.25 hours. At theconclusion of the polymerization, as determined by GPC, traces ofunreacted monomer were removed by distillation under reduced pressure.The composition of the purified polymer was verified by IR and NMR. Thepolymer was shown to melt at 55.degree. C. as determined by DSC.

EXAMPLE 3

Preparation of Partially Absorbable, Fiber-reinforced Composite SiliconeElastomers as an Intravaginal Ring-General Method

Listed below are the components of an active matrix that are mixed andintroduced into a closed, 2-part Teflon mold having a ring-type cavity(ID=4.3 cm, OD=5.5 cm), an inlet for introducing the reactants, and anoutlet to exit displaced dry nitrogen used in pre-purging the dry mole.A circular construct (outside diameter=4.9 cm) was made as a braidedmultifilament yarn (with an average single filament diameter of 15micron) having side loops was placed centrally (by virtue of the sideloops) into the cavity of the lower component of the mold to allow forequidistant placement between the OD and ID of the curved ring system. Afraction of the components listed below, which have been mixed undernitrogen, was charged into the lower half of the open mold under anitrogen atmosphere. The top part was then placed on the lower part, andthe mold was closed and mechanically secured. The remaining fraction ofthe mixed components was then injected into the mold through the feedport.

List of Mixed Matrix Components and Filler

Two-component Silastic®

Fibrous Construct

Microparticulate Cation-exchanger (from Example 1)

Bioactive agent(s)

The charged mold is heated at 80.degree. C. for the required period oftime. At the conclusion of the heating cycle, the ring was removed andcoated, if so needed, with 95/5 poly(caprolactone-co-glycolide)(fromExample 2) by dipping in a 5 percent solution of methylene chloridefollowed by drying. The ring is then used for testing in a phosphatebuffered solution at 37.degree. C. as a function of time for: (1) thedrug release profile at pH 4.5; and (2) compressibility retentionprofile, as measured in terms of the radial deformation force (RDF) thatis required to attain a predetermined degree of deformation, using anMTS Universal Tester (858 MiniBionix) in the compression mode.

EXAMPLES 4 TO 6

Preparation of Partially Absorbable Fiber-reinforced Composite ofSilicone Elastomers as Contraceptive Intravaginal rings: SpecificExamples

Uncoated ring systems Ito III were prepared following the same generalprocedure described in Example 3 and using a mixture of ascorbic acid,iron gluconate, and PG-61 (from Example 1). The components used inpreparing these rings and the curing conditions are summarized in TableI.

TABLE I Composition Data and Curing Conditions for Intravaginal Rings Ito III Example Number 4 5 6 Ring Number I II III Silastic ® matrix: TypeQ7-6830 Q7-6830 Q7-6840 Weight of Component A, g 2.1 2.0 1.85 Weight ofComponent B, g, 2.1 2.0 1.85 Fiber-reinforcing Construct^(a), mg 150 300300 Cation-exchanger^(b), mg 171 165 152 Active ingredients: Ascorbicacid, mg 343 330 304 Fe gluconate, mg 320 330 304 Dye (D&C Violet #2),mg 5 5 3.8 Curing Cycle Temperature/Time, ° C./hour 80/15.5 80/4 80/4^(a)Braided copolymeric l-lactide braided suture made of segmented 88/12l-lactide/trimethylene carbonate as described in U.S. Pat. No.6,342,065. ^(b)PG-61 from Example 1

EXAMPLE 7

Preparation of Partially Absorbable Fiber-reinforced Composite ofSilicone Elastomers as Antimicrobial Intravaginal Ring IV

Uncoated Ring IV, was prepared following the same general proceduredescribed in Example 3 and using Metronidazole as the bioactive agent.The components used in preparing this ring and curing conditions aresummarized in Table II.

Ring Number IV Ring Composition Silastic ® matrix: Type Q7-4840 Weightof Component A, g 2.3 Weight of Component B, g, 2.3 Fiber-reinforcingConstruct^(a), mg 300 Cation-exchanger^(b), mg 7 Active ingredient,Metronidazole, mg. 137 Dye (D&C Violet #2), mg 3.8 Curing CycleTemperature/Time, ° C./hour 80/4 ^(a)Braided copolymeric l-lactidebraided suture made of segmented 88/12 l-lactide/trimethylene carbonateas described in U.S. Pat. No. 6,342,065. ^(b)PG-61 from Example 1

EXAMPLE 8

Radial Deformation Force (RDF) Measurement for Evaluating RingCompressibility: General Method

The initial compressibility of the ring and percent retention, duringincubation in a phosphate buffered solution to simulate the biologicalenvironment, was measured in terms of the force (in Newtons) required todeform the ring, radially, by 2.54 cm. The initial compressibility wasconducted by placing the ring in the lower component of the sampleholder of an MTS Universal Tester (MiniBionix, Model 858) and measuringthe force required to deform the upper part of the ring, radially, for adistance of 2.54 cm through the downward movement at a rate of 1 mm/sec,of the free, flat upper component of the sample holder.

To determine the percent retention of ring incubated in a bufferedsolution at pH 4.5 and 37.degree. C., the test ring was removed at thedesired period, wiped with tissue paper to remove excess moisture, andthe force of deformation at time “t” (Ft) was measured as noted abovefor the initial deformation force (Fo) testing. The percent strengthretention, in terms of decrease of the RDF, was calculated as follows:

% RDF retention=(Fo−Ft÷Fo)×100.

TABLE III Typical Radial Deformation Force (RDF) Values and In VitroRetention Data of Partially Absorbable Intravaginal Rings In vitro^(a)Retention of Ring From Example RDF, N RDF (% @day) II 5 1.66 82/2  III 62.26 79/14 IV 7 1.52 89/10 ^(a)Using a phosphate buffer at pH 4.5 and37° C.

EXAMPLE 9

Determination of Daily and Cumulative In Vitro Release Rates of AscorbicAcid and Ferrous Gluconate from Eluates of a Typical Contraceptive RingSystem

I. Outline of the Experimental Procedure

The procedure consists of: (1) cutting pieces of a typical ring system(as in Examples 10, 12, 19, 20, and 21) and recording the weight (piecesare placed in separate, labelled Petri dishes); (2) placing the piecesof the ring containing ferrous gluconate into a shaker containing 5 mLof phosphate buffered saline or water to Petri dishes, sealing withparafilm, and incubating at 37.degree. C. overnight; (3) collecting theeluate and measuring the volume each day, then transferring the ringpieces to a new Petri plate in 5 mL of fresh phosphate buffered salineand following Step (2) above; (4) continuing the above procedure dailyfor 2-days, then drying the residual matrix and recording the finalweight; and (5) determining the amount of ascorbic acid and ferrousgluconate in each daily collection of the eluate.

II. Determination of Ascorbic Acid

A. Principle: In this procedure, ascorbic acid is oxidized todehydroascorbic acid and the latter is coupled with2,4-dinitrophenylhydrazine. The coupling reaction forms the2,4-dinitrophnylosazone of dehydroascorbic acid, a light browncrystalline compound. When treated with 85% H.sub.2SO.sub.4, the osazoneis rearranged to form a reddish colored compound, which absorbsmaximally at 500 to 550 m.mu.. It is a highly stable product under theconditions used and is well suited for calorimetric measurement.

B. Preparation of Reagents:

Reagents used included (1) trichloroacetic acid solutions, 4%; (2)2,4-dinitrophenylhydrazine reagent (2.0 g of 2,4-dinitrophenylhydrazinewere dissolved in 100 mL 9N H.sub.2SO.sub.4 [1 part of concentratedH.sub.2SO.sub.4 plus 3 parts water], 4 g of reagent thiourea were added,shaken occasionally, dissolved, filtered and then refrigerated; and (3)ascorbic acid solutions.

Stock Solution: Ascorbic acid of the highest purity (12.5 mg) isdissolved in 50 mL of 0.5% oxalic acid. This solution is oxidized byadding one teaspoon (or 1 g) of acid-washed Norite (activated carbon)per 50 mL, shaking thoroughly, and filtering through Whatman No. 42filter paper. One mL of this solution contains 10 .mu.g ofdehydroascorbic acid. Keep refrigerated.

Standard Solution of Dehydroascorbic Acid: To prepare the Standard CurveSolutions, dilute the dehydroascorbic stock solution with 4.0%trichloroacetic acid. The dilutions will serve for a range of 20 to 200mg of ascorbic acid per liter of solution.

C. Procedure:

Two mL of Norite filtrate of unknowns, 2 mL of the dehydroascrobic acidstandard solution, and 2 mL of 4% TCA (control tube) are added to glasstubes. Then 0.5 mL of 2,4-dinitrophenylhydrazine reagent is added toeach tube. The tubes are placed in a constant temperature water bath at37.degree. C. The tubes are kept immersed in the bath for approximately1.5 hours, removed, and subsequently placed in a beaker of ice watercontaining generous quantities of ice. To each of the tubes in the icewater bath is added slowly 2.5 mL of 85% H.sub.2SO.sub.4. The tubes areshaken under the ice water to obtain complete mixing and are thenremoved to a rack. After 30 minutes, the tubes are wiped and cleaned torecord the absorbance in a colorimeter, using 540 m.mu. filter. To takethe reading, the control tube is used to set the colorimeter at 100%transmittance or zero absorbance.

III. Determination of Ferrous Gluconate

A. Materials and Methods:

The samples assayed for ferrous gluconate were taken from the solutions,which contained the Ovaprene ring over various periods of time. Reagentsused for the assay were phosphate buffered saline, pH 7.4 (PBS),1,10-Phenanthroline, sodium acetate (anhydrous), and bromophenol bluedye (pH 3.0-4.6) (Sigma), hydroquinone and acetic acid (Aldrich), andferrous gluconate (Alfa Aesar). Spectronic 20 Genesys™ Spectrophotometerwas used to read the solution absorbance.

The reagents for the assay were prepared as follows:

1. Phosphate buffered saline (PBS)-add one packet to 1000 ml ofdistilled water.

2. 1% solution of hydroquinone is prepared with distilled water.

3. 0.5% solution of 1,10-Phenanthroline is prepared with distilled waterand sodium acetate-acetic acid solution added to 4% final volume (Keepin dark and discard if any color develops).

4. Sodium acetate-acetic acid buffer solution (pH 4.0)-dissolve 27 g ofanhydrous sodium acetate in 50 ml of distilled water. Then add 24 ml ofacetic acid and bring to a final volume of 100 ml with distilled water.

5. 1 mM solution of ferrous gluconate standard is prepared with PBS.

6. A 1 mg/ml solution of bromophenol blue dye is prepared with distilledwater.

B. Procedure:

For the ferrous gluconate standard curve, 1 mM ferrous gluconatestandard solution was diluted with PBS to produce the following finalconcentrations: 0.75 mM, 0.5 mM, and 0.25 mM.

The assay was performed by adding 600 .mu.l of the standard curvesolutions and 600 .mu.l of each ring buffer to be assayed to 5-ml glasstubes. The control tube was 600 .mu.l of PBS. Using a Pasteur pipetteone drop f bromophenol blue and one drop of sodium acetate solution wasadded to each tube, followed by the addition of 1 ml of 1% hydroquinoneand 1 ml of 0.5% 1,10-Phenanthroline. The tubes were gently vortexed andincubated at 50.degree. C. for 2 hr. Using a spectrophotometer, thetransmittance for each tube was read at 408 nm.

EXAMPLE 10

Determination of the Initial Release Profile of Metronidazole fromAntimicrobial Ring IV

Specimens of Ring IV made as described in Example 7 were placed in aphosphate buffer at 37.degree. C. and pH 4.5. The concentration ofreleased Metronidazole was determined over an eight-day period. Analysisof Metronidazole was conducted on day 2, 3, 6, and 8 and the buffer wasreplaced with fresh aliquots at each of these periods. The cumulativepercent release data are summarized below:

Study Period, day 2 3 6 8 Cumulative % Release 4.3 5.2 7.4 8.8

Preferred embodiments of the invention have been described usingspecific terms and devices. The words and terms used are forillustrative purposes only. The words and terms are words and terms ofdescription, rather than of limitation. It is to be understood thatchanges and variations may be made by those of ordinary skill artwithout departing from the spirit or scope of the invention, which isset forth in the following claims. In addition it should be understoodthat aspects of the various embodiments may be interchanged in whole orin part. Therefore, the spirit and scope of the appended claims shouldnot be limited to descriptions and examples herein.

What is claimed is:
 1. A partially absorbable, fiber-reinforcedcomposite for the controlled delivery of at least one bioactive agentcomprising an absorbable fiber construct within a biostable elastomeric,copolymeric matrix, the matrix further containing an absorbablemicroparticulate ion-exchanging polymer to modulate the release of saidbioactive agent for a desired period of time at a specific biologicalsite, the fiber construct capable of providing time-dependent mechanicalproperties.